Background

Progressive familial intrahepatic cholestasis (PFIC) is a class of chronic cholestasis disorders that begin in infancy and usually progress to cirrhosis within the first decade of life. The average age at onset is 3 months, although some patients do not develop jaundice until later, even as late as adolescence. PFIC can progress rapidly and cause cirrhosis during infancy or may progress relatively slowly with minimal scarring well into adolescence. Few patients have survived into the third decade of life without treatment.
[1, 2]

Initially described in Amish descendants of Jacob Byler, PFIC was originally named Byler disease. The condition was inherited in an autosomal recessive manner and was characterized by hepatocellular cholestasis. Subsequently, numerous phenotypically similar non-Amish patients were reported, and the term Byler syndrome was used to describe these patients' condition. These terms now have been superseded by the term progressive familial intrahepatic cholestasis.

At present, specific gene defects have been identified for 3 subtypes of PFIC (see Table 1 below). PFIC1 (the former Byler disease) and PFIC2 are characterized by low gamma-glutamyl peptidase (GGT) levels. Despite their genetic distinctiveness, PFIC1 and PFIC2 have few clinical differences, and both are caused by the absence of a gene product required for canalicular export and bile formation.

In PFIC3, patients have a similar clinical presentation, but laboratory results reveal an elevated serum GGT. Rather than defective bile acid export, patients with PFIC3 have deficient hepatocellular phospholipid export. The lack of phospholipids produces unstable micelles that have a toxic effect on the bile ducts, leading to bile duct plugs and biliary obstruction.

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Pathophysiology

The primary mechanism of disease in patients with PFIC1-2 is a defect in canalicular bile acid transport with primary retention of hydrophobic bile salts. This conclusion is supported by the differences in the quantitative and qualitative distribution of bile acids in serum and bile. Total serum bile acid concentrations are markedly elevated (i.e., usually >200 mmol/L compared to normal concentrations of < 10 mmol/L). Total biliary bile acid concentrations are low (i.e., 0.1-0.3 mmol/L, compared with normal concentrations of >20 mmol/L) and have a predominance of cholic acid conjugates. These findings suggest a defect in biliary excretion, particularly of chenodeoxycholic acid conjugates.

PFIC1 is caused by a genetic mutation in the ATP8B1 gene on chromosome 18q21-22. This gene encodes the protein FIC1, also known as ATP8B1. FIC1 is a P-type ATPase responsible for maintaining a high concentration of phospholipids in the inner hepatocyte membrane. The mechanism whereby the loss of FIC1 activity results in defective bile salts excretion is unknown, but it has been hypothesized that a mutation in this protein causes phospholipid membrane instability leading to reduced function of bile acid transporters.
[3]

PFIC2 is caused by a mutation in the ABCB11 gene on chromosome 2q24 that encodes the bile salt export pump (BSEP). BSEP is the major canalicular bile acid pump, and thus the loss of BSEP function results in severe hepatocellular cholestasis.
[4] In a immunohistochemical study, BSEP was not detected in the canalicular membrane in PFIC patients having ABCB11 mutation, in contrast to patients with PFIC1 or PFIC3. This suggests that in most patients with PFIC-2, the gene defect is sufficiently severe to produce no product or a protein that cannot be inserted into the canalicular membrane.
[1]

While the PFIC1 and PFIC2 involve a defect in bile acid secretion, PFIC3 involves a defect in phospholipid secretion. In PFIC3, a mutation in the gene ABCB4 on chromosome 7q21 encodes the protein MDR3, which functions in the translocation of phosphatidylcholine across the canalicular membrane.
[5, 6, 7] Bile from patients with PFIC3 has very low concentrations of phospholipid. In an animal model of PFIC3, Abcb4 (Mdr2) knockout mice cannot excrete phospholipid into bile and develop progressive liver disease characterized by portal inflammation, proliferation of bile ducts, and fibrosis. This phenotype is rescued by transgenic expression of the human ABCB4 gene, confirming that phospholipid excretion is dependent on ABCB4. Functional loss of this gene results in cholestatic liver disease.

The biliary damage in PFIC3 is due to the absence of phospholipid in the ductular lumen. The stability of mixed micelles is determined by a 3-phase system in which a proper proportion of bile salts and phospholipid are necessary to maintain solubility of cholesterol. The absence of phospholipid destabilizes micelles and promotes lithogenic bile with crystallized cholesterol, which could produce small bile duct obstruction.

The absence of bile salts in the bile ducts in PFIC1 and PFIC2 and their presence in the bile ducts in PFIC3 accounts for the difference in biochemical tests. In PFIC3, as in most cholestatic diseases, prolonged exposure of the duct cell membranes to bile salts results in solubilization of GGT, absorption of the enzyme into the circulation, and elevated GGT levels on serum tests. In contrast, in PFIC1 and PFIC2 there are low levels of biliary bile salts, the GGT is never solubilized, and the serum GGT is normal.

Several clinical differences have been reported between patients with PFIC1-3. Clinically, patients with PFIC1 and PFIC2 present with jaundice and severe pruritus in the first few months of life. Patients with PFIC1 may experience a relapsing and remitting course of symptoms, but permanent cholestasis, fibrosis, and liver failure are inevitable without treatment. PFIC1 is also associated with watery diarrhea. This secretory diarrhea may persist after liver transplantation and may reflect an important role for FIC1 in the intestine, where it is highly expressed. Other extrahepatic manifestations associated with PFIC1 include short stature, sensorineural deafness, pancreatitis, and hepatic steatosis.

Mutations in the ATP8B1 gene also cause a less severe form of cholestasis, known as benign recurrent intrahepatic cholestasis type 1 (BRIC1). BRIC1 is characterized by episodic jaundice and pruritus that resolve with no progression to liver failure. Genotype-phenotype correlation between PFIC1 and BRIC1 is imperfect, although mutations predicted to have a more severe effect on protein function (eg, nonsense, frameshifts, deletions) are more common in PFIC1. This suggests that other modifier genes may also play a role.

In a manner similar to PFIC1/BRIC1, BRIC2 is a benign cholestatic disease associated with ABCB11 mutations. In this case, the genotype-phenotype correlation is more clear, with mutations in patients with BRIC2 resulting in more mild loss of protein function that those found in patients with PFIC2. In practice, there is likely to be a spectrum of disease for both PFIC1/BRIC1 and PFIC2/BRIC2, with patients having intermediate levels of cholestasis and long-term complications.

PFIC2 is associated with a continuous course of symptoms, in contrast to the episodic pattern seen in PFIC1. Once cholestasis develops, patients rapidly progress to liver failure within several years. Consistent with the restricted expression of ABCB11 to the liver, there are no extrahepatic manifestations of PFIC2. However, PFIC2 is associated with hepatocellular carcinoma in children. One case series identified 11 children with clinically diagnosed PFIC and hepatocellular carcinoma. Retrospective immunohistochemical analysis with anti-BSEP antibody showed that 10 of these children had little or no BSEP in the canalicular membrane and genetic analysis in these 10 children revealed ABCB11 mutations. The exact mechanism of carcinogenesis is unknown; however, this risk stresses the importance of determining the type of PFIC on diagnosis.

Only one third of patients with PFIC3 present with cholestasis during infancy; the rest become symptomatic in childhood and adolescence. The pruritus tends to be less severe than in PFIC1 and PFIC2, but progression to biliary cirrhosis and liver failure is still rapid.

Decreased phospholipid concentration in bile leads to destabilized micelles within ductules causing inflammation/destruction and eventually cholestasis

High

Onset of cholestasis tends to be later in life

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Epidemiology

Frequency

United States

PFIC types 1 and 2 are rare, but the exact frequency is unknown. Incidence is estimated at 1:50,000 to 1:100,000 births.
[1] Fewer than 200 patients with PFIC1 or PFIC2 are reported in the medical literature or are otherwise known to the authors. PFIC3 is even rarer, with fewer than 20 reported patients. Both have a greater frequency in some cultures in which consanguineous marriage is common.

Mortality/Morbidity

All forms of progressive familial intrahepatic cholestasis are lethal in childhood unless treated. They can be rapidly progressive and result in cirrhosis during infancy, or they may progress relatively slowly well into adolescence and cause minimal scarring. Few patients have survived into the third decade of life without treatment.

Morbidity is the result of chronic cholestasis (see Medscape Reference article Cholestasis). Pruritus is more pronounced in PFIC types 1 and 2 and often occurs out of proportion to the level of jaundice, which is often low grade and can wax and wane. The pruritus may be disabling and usually does not respond to medical therapy.

Growth failure is another major feature of progressive familial intrahepatic cholestasis. More than 95% of patients have short stature. Perennial asthma like disease and recurrent epistaxis in the absence of thrombocytopenia or coagulopathy are common problems, probably caused by exceedingly high circulating levels of bile salts. Fat-soluble vitamin deficiencies are prevalent in untreated patients. As many as one third have cholelithiasis. Most patients have hepatomegaly, whereas significant splenomegaly implies advanced fibrosis or cirrhosis. These patients do not have xanthomas.

PFIC2 is associated with an increased risk of developing hepatocellular or cholangiocarcinoma carcinoma early in life.
[8] Although a standard frequency of screening for HCC has not been established, it is reasonable to measure the serum alpha-fetoprotein levels and perform a hepatic ultrasound every 6 months.[5]

Race

PFIC types 1 and 2 have been reported in all races. PFIC3 has been found in Western European, White, and North African Arabic populations.

Stefano Guandalini, MD Founder and Medical Director, Celiac Disease Center, Chief, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Chicago Medical Center; Professor, Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Division of the Biological Sciences, The Pritzker School of Medicine

Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching. for: Abbott Nutritional, Abbvie, speakers' bureau.